DESCRIPTION: It is well known that the kidney plays a central role in the regulation of sodium excretion and thereby in the control of blood volume and blood pressure. However, the mechanisms underlying this blood pressure dependent control of sodium excretion remains largely unknown. The characterization of these mechanisms is extremely important in understanding not only the physiology of sodium excretion but also the manner in which the derangement of these homeostatic mechanisms lead to the development of hypertension. The overall goal of the proposal of Dr. Granger is to characterize the renal mechanisms that link changes of renal perfusion to sodium excretion. There are six groups of studies which are designed to elucidate interrelated problems: The first intends to establish if the urinary excretion of nitric oxide (NO) and nitrate (NO3) as well as the excretion of cGMP correlates with the progressive elevation of sodium excretion which are elicited by step graded elevation of renal perfusion pressure. It is claimed that this will disclose the extent to which NO mediates pressure natriuresis by allowing the transmission of perfusion pressure to the renal interstitium. The second group of studies intends to see if the administration of L-arginine (a precursor of NO synthesis) restores pressure natriuresis in the Dahl sensitive rats by increasing papillary blood flow. With this purpose, papillary blood flow and vasa recta hydrostatic pressure are determined in salt sensitive and resistant rats before and after the intravenous- or intraperitoneal-administration of L-arginine. The role of NO is also examined by determining in salt resistant rats the extent to which the blockade of NO synthesis with L- NAME impairs the effect of renal perfusion pressure on renal hemodynamics and sodium excretion when the inhibitor is given via a renal interstitial (implanted) catheter for one hour prior to the study. This observation is complemented with a series of micropuncture studies which will yield important information on the nephron segment that is involved in the changes of sodium reabsorption observed during the induced alterations of NO synthesis. The third group of studies intends to know if the blockade of NO synthesis with L-NAME inhibitors in the Dahl resistant rats makes them salt sensitive. In this protocol, the inhibitor of NO synthesis will be infused into the renal interstitium via implanted renomedullary catheters. The infusion will be performed from 7-10 days. Changes in sodium intake will define if blood pressure has been dependent on volume expansion. The fourth group of studies deals with the interesting problem of knowing why Dahl salt sensitive rats show sodium excretion hyporesponsiveness to changes in renal interstitial pressure induced by renal fluid volume expansion. It is suggested that these animals have a deficient synthesis of PGE2 and that this compound could play an important role mediating pressure natriuresis either directly or by controlling the back leak of the tight junction. Back leak of the tight junction is determined in a separate group of studies (protocol 4b) by measuring Lanthanum fluxes from the renal interstitium to the lumen of proximal tubules. The fifth group deals with a different issue which is the importance that endothelin plays in contributing to the abnormal pressure natriuresis mechanism in various forms of hypertension. The author suggests that as hypertension becomes established and endothelin dysfunction or damage occurs, endothelin plays a greater role in the progression of the disease. The assumption is supported by preliminary studies showing the blockade of endothelin receptors A or B produces a decrease in SHR rats. The ability of different endothelin receptor blockers to normalize renal function and sodium excretion is studied in this section. This section is complemented with a group of studies included under the section six where it is investigated the extent to which chronic infusion of endothelin receptor antagonists lead to a long term reduction in arterial pressure in various forms of hypertension, such as SHR, DOCA salt, etc.